Cold pain after eating fish

Hypersensitivity caused by ciguatoxin poisoning

An uncomfortable indisposition caused by a neurotoxin may arise suddenly after a pleasant fish dinner without any warning. Even after a long time, nerves continue to report a painful cold sensation at temperatures that would have previously felt cool and refreshing. This is a typical symptom of ciguatera tropical fish poisoning. A group of scientists from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and a team from the University of Queensland in Brisbane, Australia, have discovered the mechanism which causes this hypersensitivity. The poison causes cold thermoreceptors to sense pain prematurely, even if there is no due cause. The respected ‘EMBO Journal’ has already reported these findings online and is planning to publish a print version soon.

Ciguatera is the most common form of fish poisoning in the world. Yet this type of poisoning is not caused by spoilt or naturally poisonous fish as may be expected – it is caused by the ingestion of otherwise harmless fish dinners. The cause of this fish poisoning are so-called ciguatoxins, which originate from single-celled flagellates (dinoflagellates) that grow as epiphytes on algae and seaweed on coral reefs. The poison is enriched throughout the food chain and reaches its highest concentrations in large reef predators. In the end it is humans that suffer, as fish are unaffected by the powerful neurotoxin for reasons which are as of yet unknown.

Contaminated predatory fish are difficult to tell apart from non-poisonous specimens, and the number of affected species is large. As the first symptoms occur quite quickly, an idyllic holiday on the white sands of a tropical island could easily become a nightmare after sampling freshly-caught local fish: while the poison initially causes nausea, vomiting, abdominal pain and diarrhoea, these symptoms begin to fade after a few days and are replaced with neurological symptoms and a wide range of pain symptoms, which may prevail for months or even years. There is currently no specific treatment.

A notable characteristic of the poisoning is that it causes painful burning or tingling sensations in the hands and feet as well as the mouth in response to cold. This can be caused by a cool breeze (which would usually feel pleasant) or swallowing cold food or drinks. Almost every patient suffering from this type of poisoning reports this painful hypersensitivity to cold, which is also known to neurologists as cold allodynia. Alcohol consumption intensifies these symptoms.

Despite the devastating effects it has on humans, chemists are fascinated by the complex molecular structure of ciguatoxin, which, depending on the season, can be found in various forms in the Indian, Pacific and Caribbean Oceans. It consists of between 11 and 14 different rings which can have anything from five to nine members. Ciguatoxin is a lipid-soluble polyether compound with more than 28 chirality centres – significant points in a spatial arrangement of molecules in which they are not superposable despite their identical structure – and can be connected to other rings by a single atom (spiro compound). Neither heat, freezing or exposure to acid can destroy the toxin. This is an impressive feat for the minuscule and ancient dinoflagellate Gambierdiscus toxicus and an example of powerful chemical synthesis. It was not before 2001 that Japanese chemists were able to copy the single-cell organism and recreate the complicated molecule in a laboratory.

The toxin attacks the sodium channels on voltage-dependent nerve membranes such as those found in the pain-sensitive nerve endings in the skin. From here, signals in the form of electrical nerve impulses (action potential) are transmitted to the brain to report, for instance, the threat of tissue damage. Researchers have been aware for almost 30 years that the ciguatoxin poison activates these channels irreversibly, but how this can result in such painful hypersensitivity in response to cold temperatures was previously unknown. The team of researchers from Germany and Australia have found that the known cold thermoreceptor TRPA1 becomes greatly sensitised when the sodium channels are activated. Under normal circumstances, TPRA1 usually opens at temperatures below 10°C and then activates the sodium channels to warn the body of impending tissue damage caused by cold temperatures. If this receptor is triggered by hyperactive sodium channels, however, it transmits cold burning pain at cool temperatures that would usually be perceived as pleasant.

The researchers observed the toxin causing hypersensitivity to temperatures in the TRPA1 cold receptor during experiments on cells in petri dishes. They realised that it was the neurons expressing TRPA1 that had the highest sensitivity to the toxin.  In a simplified cell model, the researchers found that TRPA1 was not directly activated by the poison ciguatoxin.  The receptor only exhibits hypersensitivity to drops in temperature if there is a sodium channel in the cell membrane. ‘This causes temperatures that are just under the regular skin temperature of 32°C to be perceived as just as painful as temperatures approaching freezing point,’ explains Dr. Irina Vetter from the Institute of Molecular Biosciences at the University of Queensland.

The TRPA1 receptor is also located in the ultra-thin endings of the pain fibres in the lowest layers of the epidermis, which are affected directly by external temperature changes. Dr. Katharina Zimmermann from the Institute for Physiology and Pathophysiology at FAU was able to detect electrical impulses from these nerve fibres in mice, allowing her to investigate the effect of ciguatoxin on the sensory nerve endings. Dr. Zimmermann discovered that the effect of the toxin was significantly weaker in mice without TRPA1 receptors. By studying the behaviour of the mice, the researchers demonstrated that mice without the TRPA1 receptors were almost immune to developing the cold burning sensation caused by the toxin.

The project was an excellent showcase of cooperation between the research group led by Prof. Dr. Peter Reeh and PD Dr. Zimmermann at the Institute of Physiology and Pathophysiology with the pharmacologist and specialist for functional imaging PD Dr. Andreas Hess (Institute for Pharmacology and Toxicology at FAU). Dr. Hess was able to use fMRI in mice brains to prove that mice without TRPA1 receptors were less susceptible to cold temperatures even before being exposed to the toxin. This was a new discovery – conventional behaviour tests in mice are not sensitive enough to reveal such marginal differences. Dr. Hess observed that this deficit in the perception of cold temperatures is reduced even further after the pain-inducing toxin is introduced into the mice.

The study concluded that the cold thermoreceptor TRPA1 can become so hypersensitive in comparable circumstances resulting from other diseases (such as neuropathological pain) that patients can experience similar painful burning sensations from a drop in temperature.  The researchers also believe that the current clinical trial of TRPA1 blockers could help to significantly alleviate the symptoms of ciguatera poisoning among patients.

The research project was supported financially by the DAAD, the Staedtler foundation and other organisations.

Contact:

Associate Professor Dr. Katharina Zimmermann
Institute for Physiology and Pathophysiology
Phone: +49 9131 85 22491
zimmermann@physiologie1.uni-erlangen.de